Anti-platelet agents

Dr. J Pradeep

Contents

• Introduction• Classification• Individual drugs• Newer anti-platelet agents• Summary

Introduction

• Normal hemostasis – Maintenance of blood in a fluid, clot-free state in

normal vessels; and– Formation of hemostatic plug at a site of vascular

injury.• Opposite : Thrombosis– Thrombi are lysed and blood is made fluid by

fibrinolytic system

• Both hemostasis and thrombosis are regulated by three general components

– The vascular wall, –Platelets, and – The coagulation cascade

• Platelet count:150000 - 400000/mm3• Lifespan: 7-10 days• No nucleus• Cannot synthesise proteins• Shape: biconcave discs, fully spread cells

• Receptors on platelets: – GpIa/IIa: receptors for collagen – GpIb: receptor for vWF– GpIIb/IIIa: receptor for fibrinogen– P2Y1/P2Y12: purinergic receptors for ADP– PAR1/PAR4: protease activated receptors for

thrombin (IIa)

• Platelets provide the initial hemostatic plug at sites of vascular injury

• They also participate in pathological

thromboses that lead to myocardial infarction, stroke, and peripheral vascular thromboses

Platelet adhesion and aggregation

Classification

• TXA2 inhibitors – Aspirin (non selective COX inhibitor)

• Phosphodiesterase inhibitors – Dipyridamole

• Thienopyridine derivatives – Ticlopidine, Clopidogrel, Prasugrel

• Glycoprotein (GP) IIb/IIIa inhibitor – Abciximab, Eptifibatide, Tirofiban

• Newer anti-platelet agents – Cangrelor, Ticagrelor, SCH530348

Aspirin

• Aspirin blocks production of TxA2by acetylating a serine residue near the active site of platelet cyclooxygenase-1 (COX-1)

• The action of aspirin on platelet COX-1 is permanent

• Action lasts for the life of the platelet (7-10 days)

• Cumulative effect on repeated doses • Should be stopped atleast one week prior to

any surgical procedure• Complete inactivation of platelet COX-1 is

achieved with a daily aspirin dose of 75 mg• Maximal effective doses is 50-320 mg/day

• Anti-thrombotic dose is much lower than doses required for other actions

• Higher doses do not improve efficacy• Potentially less efficacious because of

inhibition of prostacyclin production• Higher doses also increase toxicity, especially

bleeding

Dipyridamole

• Interferes with platelet function by increasing the cellular concentration of cyclic AMP

• This effect is mediated by inhibition of cyclic nucleotide phosphodiesterases and Blockade of uptake of adenosine

• cAMP potentiates PGI2 and interferes with aggregation

• Dipyridamole alone has little clinically significant effect

• Inhibits embolization from prosthetic heart valves when used in combination with warfarin

• May potentiate the action of aspirin in preventing strokes in patients with TIA,

• No additional benefit as combination with aspirin in preventing MI

Ticlopidine

• Ticlopidine is a thienopyridine prodrug that inhibits the P2Y12 receptor

• Converted to the active thiol metabolite in liver

• It is rapidly absorbed and highly bioavailable• It permanently inhibits the P2Y12 receptor and

has prolonged action

• Cumulative effect is seen• Maximal inhibition of platelet aggregation is

not seen until 8-11 days after starting therapy• The usual dose is 250 mg twice daily• Like aspirin it has short half life and inhibition

of platelet aggregation lasts for few days after stopping drug

Side effects

• Common: nausea, vomiting, diarrhoea• Serious adverse effect: severe neutropenia• Fatal agranulocytosis with thrombocytopenia

has occurred within the first 3 months of therapy

• Frequent blood counts and platelet counts are advised in first few months of therapy

• Discontinue therapy if counts fall• Thrombotic thrombocytopenic purpura-

hemolytic uremic syndrome (TTP-HUS) – rare adverse effect

Therapeutic uses

• Prevention of stroke and TIAs• Intermittent claudication• Unstable angina• Prevention of MI• Preventing restenosis and stent thrombosis

after PCI

Clopidogrel

• Similar to ticlopidine• Theinopyridine pro drug with slow onset of

action (only 15% is activated by CYP3A4)• Irreversible inhibitor of platelet P2Y12

• More potent and lesser side effects• Usual dose is 75 mg/day with or without an

initial loading dose of 300 or 600 mg

• Secondary prevention of stroke : somewhat better than aspirin

• Prevention of recurrent ischemia in patients with unstable angina: better as combination with aspirin

• Synergistic with aspirin since mechanism of action is different

• Wide inter-individual variability in efficacy of clopidogrel is seen

• Genetic polymorphism in CYP2C19• Patients with reduced function of CYP219*2

allele show less inhibition of platelets by clopidogrel and have higher rate of cardiovascular events

Uses

• To reduce the rate of stroke, myocardial infarction, and death in – Patients with recent myocardial infarction or

stroke– Established peripheral arterial disease– Acute coronary syndrome

Interactions

• Proton pump inhibitors, inhibitors of CYP2C19, produce a small reduction in the inhibitory effects of clopidogrel on ADP-induced platelet aggregation

• Atorvastatin, a competitive inhibitor of CYP3A4, reduced the inhibitory effect of clopidogrel on ADP-induced platelet aggregation

Prasugrel

• Thienopyridine prodrug• Rapid onset of action• Greater inhibition of ADP induced platelet

aggregation• Almost completely absorbed from the gut• Almost all of the drug is activated

• Irrversible inhibitor of P2Y12 receptor• Has prolonged effect after discontinuation• Better than clopidogrel in reducing incidence

of non fatal MI• The incidence of stent thrombosis also was

lower with prasugrel than with clopidogrel

• However, it has higher rates of fatal and life-threatening bleeding

• Contraindicated in those with a history of cerebrovascular disease - high risk of bleeding

• Caution is required if prasugrel is used in patients weighing <60 kg or in those with renal impairment

• After a loading dose of 60 mg, prasugrel is given once daily at a dose of 10 mg

• Patients >75 years of age or weighing <60 kg may do better with a daily prasugrel dose of 5 mg

• It is reasonable alternative to clopidogrel in patients with the loss-of-function CYP2C19 allele because there is no association with decreased anti platelet action in prasugrel

Glycoprotein IIb/IIIa inhibitors

• Block final step in platelet aggregation induced by any agonist

• Abciximab• Eptifibatide• Tirofiban

Abciximab

• Abciximab is the Fab fragment of a humanized monoclonal antibody directed against the GpIIb/IIIa receptor

• Uses:– percutaneous angioplasty for coronary

thromboses– prevent restenosis, recurrent myocardial

infarction, and death: used in combination with aspirin and heparin

• T1/2: 30 min• Duration of action: 18 – 24 hrs• Dose: 0.25-mg/kg bolus followed by 0.125

g/kg/min for 12 hours or longer, IV• Adverse effects: – Hemorrhage (1-10%)– Thrombocytopenia (2%)

• Platelet transfusions can reverse the aggregation defect

• Expensive

Eptifibatide • Cyclic peptide inhibitor of the fibrinogen

binding site on GpIIb/IIIa receptor• Dose: 180 g/kg IV bolus followed by 2

g/kg/min for up to 96 hours• Short duration of action: 6-12 hrs• Given with aspirin and heparin

• Use:– Acute coronary syndrome– Angioplastic coronary interventions

• Adverse effects:– Bleeding (10%)– Thrombocytopenia (0.5-1%)

Tirofiban

• Similar to eptifibatide• Value in antiplatelet therapy after acute

myocardial infarction is limited• Used in conjunction with heparin

GpIIb/IIIa inhibitorsFeatures Abciximab Eptifibatide Tirofiban

Description Fab fragment of humanized mouse monoclonal antibody

Cyclical heptapeptide

Nonpeptide

Specific for GPIIb/IIIa

No Yes Yes

Plasma t1/2 Short Long (2.5h) Long (2.0h)

Platelet-bound t1/2

Long (days) Short (sec) Short (sec)

Renal clearance

No Yes Yes

Newer anti-platelet agents

• Cangrelor• Ticagrelor• SCH530348 • E5555

Cangrelor

• Adenosine analogue• Reversible inhibitor of P2Y12 receptor• T1/2: 3-6 min• Duration of action: 60 min• Administration: IV bolus followed by infusion• Little or no advantage over other drugs

Ticagrelor

• Orally active reversible inhibitor of P2Y12 receptor

• Rapid onset and offset of action• Twice daily dosage• First new antiplatelet drug to demonstrate a

reduction in cardiovascular death compared with clopidogrel in patients with acute coronary syndromes

SCH530348, E5555

• SCH530348 an orally active inhibitor of PAR-1, is under investigation as an adjunct to aspirin or aspirin plus clopidogrel.

• Two large phase III trials are under way. • E5555 is an oral PAR-1 antagonist in early

developement

Summary

• Potent inhibitors of platelet function have been developed in recent years

• These drugs act by discrete mechanisms; thus, in combination, their effects are additive or even synergistic

• Aspirin has remained, for over 50 years, the cornerstone of antiplatelet therapy owing to its proven clinical benefit and very good cost–effectiveness profile.

• Their availability has led to a revolution in cardiovascular medicine, whereby angioplasty and vascular stenting of lesions now are feasible with low rates of restenosis and thrombosis when effective platelet inhibition is employed

THANK YOU.

References • Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12 th

edition, Section III. Modulation of Cardiovascular Function, Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs

• Robbins and Cotran’s Pathologic basis of disease, 8th edition, Section IV, Hemodynamic disorders, Thromboembolic disease and shock. Hemostasis and thrombosis.

• Tripathi K D, essentials of medical pharmacology, 6th edition, Section ten, Drugs affecting blood and blood formation. Drugs affecting coagulation, bleeding and thrombosis.

• Kallirroi I Kalantzi, Maria E Tsoumani, ET. AL. Pharmacodynamic Properties of Antiplatelet Agents -Current Knowledge and Future Perspectives , Expert Rev Clin Pharmacol. 2012;;5(3):319- 336

Dazoxiben

• It inhibits the enzyme thromboxane synthetase so reduces the concentration of thromboxane A2

• Its antiplatelet action is not satisfactory, when used alone.

• However may be useful when used with aspirin.

PROSTACYCLINE ANALOGUES

• Ex are epoprostenol, iloprost• These group of drugs block all pathway for platelet

activation.• They also inhibits the expression of GP IIb/IIIa

receptor.• Epoprostenol has a very short half life of 3 mins so it

has to be used by iv infusion. • It causes headache and flushing due to vasodilation.• iloprost is similar to epoprostenol but iloprost is

longer acting.